Bone cement and a system for mixing and delivery thereof

ABSTRACT

A bone cement formulation stored as a solid component pack having 0.3 to 20 solid component pack weight percent of an elastomer and a polymer bead core having a polyacrylate terminated surface. The second component pack is a liquid component pack including an acrylate monomer. An alternate solid component pack includes 3 to 25 solid component pack weight percent of a polyacrylate and a rubber toughened polymethyl methacrylate. A cement mixing and delivering system according to the present invention includes a tube having an exit nozzle and an aperture. An end plate is adapted to seal against the interior of the tube aperture and the end plate has a plurality of needles protruding therefrom into the tube. A rotatable and slidable divider is received within the tube intermediate between the end plate and the exit nozzle. The divider includes at least two plates. Each of the plates has a plurality of apertures that upon alignment the needles of the first plate are urged through the apertures of the at least two divider plates.

FIELD OF THE INVENTION

[0001] The present invention relates generally to orthopedic adhesivesand, more particularly, to rubber toughened bone cement formulations.

BACKGROUND OF THE INVENTION

[0002] A milestone achievement in the bone cement surgery was Chamley'sdevelopment of polymethyl methacrylate (PMMA) bone cement used forartificial joint fixation in 1959.¹ Almost forty years later, PMMAremains the standard material for anchoring total joint implants to theskeleton. During this time, there have been numerous improvements inprosthesis design and implantation techniques to improve the clinical,restorative and rehabilitative aspects of the total hip arthroplasties.The success rate of cemented hip arthroplasties at 10 years exceeds 90%in patients aged 60 years or more when proper cementing techniques areused.² However, despite the improvements, PMMA has several recognizedshortcomings as a structural material. Aseptic loosening remains themajor long-term problem with total joint replacement.

[0003] In a bone cement system, there are three different materials(bone, cement, and implant) and two interfaces (bone and bone cement,bone cement and implant). The properties at the interfaces aremismatched because the cement is much weaker than the bone and theimplant. Fatigue and fracture of cement were implicated in the failureof these devices. Loosened prostheses, as defined by Harris et al.³generally require revision surgery. The total cost of a primary totalhip arthroplasty is substantial. The cost of revision surgery may beeven greater. The life expectancy of a revised prosthesis isconsiderably lower than that of a primary prosthesis⁴; furthermore, thetrauma and pain associated with the primary prosthesis failure, and therevision operation, are taxing on the patient. The reduction of thefailure rate in joint arthroplasty, therefore, is a primary goal ofbiomechanics and biomaterials research.

[0004] Classic bone cements are bi-component materials, which arecomposed of MMA, PMMA, initiators and filler. The solid material forms aplastic paste upon mixing with the liquid phase, usually under vacuum,with a specially designed apparatus. This viscous paste is thentransferred into the human body between the prosthesis and bone using acement delivery system. During this time, the paste solidifies,increasing its mechanical strength progressively up to saturation.

[0005] Ever since the introduction of surgical bone cements, there havebeen many efforts to improve their mechanical properties. Steps toimprove the strengths of bone cement have been categorized into variousdistinctly divergent paths. Addition of reinforcing fiber, designing ofnew mixing and delivery methods, modifying the powder or liquidcomponents, bioactive cements, and even cementless technology^(5, 6) aremajor fields of focus. Even though there have been some remarkableimprovements in bone cement technologies for clinical application,however, not all efforts to produce superior quality bone cement fortotal joint replacement have so far been successful.

[0006] Efforts to improve bone cement properties have been extensive.These efforts largely have involved modification of monomer componentsand cross linkers. Pascual et al.⁽¹⁸⁾ replaced up to 20%, of the monomermethylmethacrylate (MMA) with the same amount of ethoxytriethyleneglycol monomethacrylate (TEG). They found that the addition of this newmonomer decreased noticeably the maximum temperature and increased bothsetting and working times. Mechanical testing revealed that theintroduction of TEG gave rise to a less fragile bone cement byincreasing slightly the total deformation without any change in the restof the tensile parameters.

[0007] Crosslinking agents, usually bifunctional dimethacrylates, wereused to try to improve the mechanical properties of the acrylic bonecements. At low concentrations of crosslinking agents, the mechanicalproperties were superior but steadily decreased with increasingconcentration. Poly(ethyleneglycol dimethacrylate), EGDMA(400), evenwhen used at very low concentrations., produced a steady improvement inthe mechanical properties and could be used in cement formulations witha view to reducing creep and improving mechanical properties.⁽¹⁹⁾

[0008] The same strategy has been applied to PEMA bone cement.⁽²⁰⁾Incorporation of triethylene glycol dimethacrylate produced an increasein the tensile strength and modulus with a decrease in the strain atmaximum stress. However, polyethylene glycol dimethacrylate (n=400) didnot improve the mechanical properties appreciably.

[0009] 4-methacryloyloxyethyl trimellitate anhydride (4-META) has beenadded to monomer component as an adhesion promoting agent. Implantationof the 4-META cement in animals demonstrated that these cements did notdisturb bone ingrowth and the new bone was able to contact the cementdirectly.⁽²¹⁾ A methacrylic monomer derived from salicylic acid,5-hydroxy-2-methacrylamidobenzoic acid (5-HMA), was incorporated with2-hydroxyethyl methacrylate, (HEMA), in different proportions to theliquid phase of acrylic bone cement formulations.⁽²²⁾ 5-HMA monomershows the ability to form molecular complexes with calcium atoms inorder to improve osteointegration in the application of bone cementformulations. Lower peak temperature values were observed when 5-HMA wasincorporated with respect to PMMA bone cement.

[0010] Hydroxypropyl methacrylate (HPMA) was also one of the candidatesto modify bone cements. However, the adhesion properties wereunsatisfactory. The problem was solved by increasing the monomer topolymer ratio from 1:2 to 1:1.86.⁽²³⁾

[0011] Radiopaque iodine-containing methacrylate, 2,5-diiodo-8-quinolylmethacrylate and 5,7-diiodo-8-quinolyl methacrylate have been used inthe preparation of acrylic radiopaque cements.⁽²⁴⁾ The addition of 5 wt% of the iodine-containing methacrylate provided a significant increasein the tensile strength, fracture toughness and ductility, with respectto the barium sulfate-containing cement, since no organic/inorganicinterface exist in this system.

[0012] Polybutyl methacrylate (PBMA) and polyethyl methacrylate (PEMA)have been used to replace PMMA.⁽²⁵⁾ Butyl methacrylate monomer wasbelieved to be slightly less toxic than methyl methacrylate monomer. Thesurface appearance of the broken cement from the two materials differedsignificantly, showing a series of elevations resembling tightly packedspheres in the case of PMMA, but a smooth surface with only occasionalsmooth elevations in the case of PEMBMA. PBMA and PEMA modified bonecement also show less bone necrosis and a thinner fibrous tissue layeradjacent to the cement when it is cured intraosseously.

[0013] Bone cement formulated from polybutyl methacrylate in amethacrylate matrix (PBMMA) can reduce the modulus of the materials.⁽²⁶⁾However, it has much greater long-term subsidence of the implantsystem.⁽²⁷⁾

[0014] Although polyethyl methacrylate (PEMA) offers a promisingalternative to PMMA due to its high ductility, low toxicity and lowexotherm, the fatigue test revealed that specimens made of PEMA wasinferior to the that of PMMA in term of the number of cyclic loadings tofailure. If HA is fabricated and mixed with PEMA, it can potentiallyresult in an increase in fracture toughness, fatigue crack propagationresistance, and creep resistance, without a decrease in adhesivestrength, with decrease in toxicity of acrylic cements⁽²⁹⁾, however, thecycles to failure were decreased.⁽³⁰⁾ When HA particles are treated witha silane-coupling agent, the fatigue strength is enhanced as well.⁽³¹⁾

[0015] Traditionally, poly(methyl methacrylate-co-styrene) wassynthesized by suspension polymerization.⁽³²⁾ The powder is then mixedwith barium sulfate and benzoyl peroxide. The proper formulation of thepowder package is still under observation. Synthesis of copolymers ofmethyl methacrylate-styrene with suitable compounds, particle sizedistribution, molecular weight and molecular weight distribution forbone cement application have been discussed by Cordovi et al.⁽³³⁾

[0016] Self-reinforced composite poly(methyl methacrylate) (SRC-PMMA)was developed by Wright et al. to use as a pre-coat for hip prosthesesor other stemmed prostheses.⁽³⁴⁾ This material has a similar chemicalcomposition to bone cement, with the matrix and reinforcing fibers bothfabricated from PMMA.

[0017] The elastomeric copolymer acrylonitrile-butadiene-styrene (ABS)was found to be an excellent material to enhance the mechanicalproperties of acrylic bone cement.⁽³⁵⁾ Although strength and stiffnessdecreased with an increasing second phase volume fraction, ductility andtoughness both increased. The crack propagation became stable forspecimens containing over a 5% volume fraction of the second phase. Thefracture toughness increased up to 60% when the amount of ABS reached20%. Fatigue crack propagation rate decreased by about 2 orders ofmagnitude.⁽³⁶⁾

[0018] Size of PMMA Beads

[0019] PMMA beads for bone cement application generally are made byemulsion polymerization.⁽³⁷⁾ Ginebra et al.⁽³⁸⁾ concluded that the useof relatively larger diameter PMMA beads improves the characteristicparameters of the curing process, without detrimental effects on themechanical properties of the cured cement. Pascual et al.⁽³⁹⁾ revealedthat changing the size distribution of the PMMA beads significantlychanges the curing parameters (peak temperature and setting time) of thecement formulations in comparison with the classical behavior of thecommercial systems, CMW and ROSTAL, without any noticeable loss in themechanical properties, such as tensile strength, elastic moduli,compressive strength and plastic strain.

[0020] Solutions of PMMA powder predissolved in MMA have been developedas an alternative to current powder/liquid bone cements.⁽⁴⁰⁾ Theyutilized the same addition polymerization chemistry as commercialcements, but in mixing and delivering via a closed system, porosity iseliminated and the dependence of material properties on the surgicaltechnique is decreased. The system is composed of two separate packageswith two solutions of constant polymer-to-monomer ratio, but one havingBPO initiator and the other having NNDMPT activator. The mechanicalproperties could be superior to traditional bone cements. We found thatthe shelf life is not promising for this approach.

[0021] For example, the potential advantage of increasing the mechanicalstrength of bone cement by adding fibers is offset by the increase inthe viscosity of the cement. Cementless technology is inapplicable toaged people since bone ingrowth can be difficult to achieve. Even theefforts to reduce the porosity of surgical bone cement were noteffectively linked to the long-term outcomes of total hip arthroplasty.⁷On the other hand, there is evidence that bone cement fracture does leadto a certain percentage of prosthesis failure. Therefore, in theory, animprovement in the resistance of the cement material to fracture mightalso be pivotal to perfecting the overall performance of cementedprosthesis. Thus, there exists a need for a bone cement with overallsuperior handling and mechanical properties.

[0022] The cement typically is provided in two components, powder andliquid monomer. The physician mixes the two shortly before use to form apourable liquid, which is loaded into a syringe made for the purpose.The liquid rapidly thickens into a viscous paste, requiring considerableforce for ejection from the syringe. The syringe is put into a hand-heldinjector, whereby the viscous paste can be forced out of the syringeinto the bone as detailed in U.S. Pat. No. 4,405,249.

[0023] During the operation of mixing the cement components and fillingthe syringe, bubbles of air are inevitably entrained in the liquid; whenthe liquid thickens, the bubbles cannot escape from the paste. Thebubbles of air are expressed with the cement into the bone; and when thecement hardens, the bubbles leave voids in the solidified cement. Thus,there exists a need for a cement delivery system that facilitates rapidmixing and limits bubble entrainment.

SUMMARY OF THE INVENTION

[0024] A bone cement formulation includes a solid component pack having3 to 25 solid weight component pack weight percent of a polyacrylate,and a rubber toughened polymethyl methacrylate. The bone cementformulation also includes a liquid component pack including an acrylatemonomer. An alternate cement formulation includes a solid component packcontaining 0.3 to 20 solid component pack weight percent of an elastomerand a polymer bead core having a polyacrylate terminated surface. Thiscement formulation also includes a liquid component pack including anacrylate monomer. The method for securing a prosthetic implant to a boneis detailed which includes applying an inventive bone cement formulationto the prosthesis attachment site and bringing the prosthetic implantinto contact with the inventive bone cement. A cement mixing anddelivering system according to the present invention includes a tubehaving an exit nozzle and an aperture. An end plate is adapted to sealagainst the interior of the tube aperture and the end plate has aplurality of needles protruding therefrom into the tube. A rotatable andslidable divider is received within the tube intermediate between theend plate and the exit nozzle. The divider includes at least two plates.Each of the plates has a plurality of apertures that upon alignment theneedles of the first plate are urged through the apertures of the atleast two divider plates.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025]FIG. 1 is a perspective view of an inventive cement mixing anddelivery system having two compartments divided by two plates;

[0026]FIG. 2 is a schematic illustration of the connection betweenstorage tube portions;

[0027]FIG. 3 is a partial cutaway view of the inventive cement mixingand delivery system of FIG. 1;

[0028]FIG. 4 is an end view illustration depicting the rotation patternof plates 2 and 3 of the system of FIG. 1;

[0029]FIG. 5 is a schematic showing the engagement of plate 1, 2 and 3upon alignment of the plates;

[0030]FIG. 6 is a schematic partial cutaway view illustrating thealignment of plates and tracks for cement delivery through an exitnozzle of the system depicted in FIG. 1;

[0031]FIG. 7 is an atomic force microscopy image depicting a fracturesurface of a conventional bone cement depicting a brittle breakagestructure;

[0032]FIG. 8 is an atomic force microscopy image depicting a fracturestructure conventional bone cement depicting a craze structure;

[0033]FIG. 9 is an atomic force microscopy image of an inventive bonecement depicting ductile tearing structure;

[0034]FIG. 10 is an atomic force microscopy image of an inventive bonecement depicting an elastic structure; and

[0035]FIG. 11 is a graph of residual monomer as a function of time in aninventive bone cement.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

[0036] The cement formulations of the present invention have utility ashigh mechanical strength bonding materials particularly in the area ofbone replacement, bone stabilization, and prosthesis securement. Theinventive formulations meet the mechanical property requirements of ASTMF451 while providing ease of mix, low viscosity during handling, andquick setup after injection. An inventive formulation of a polyacrylatecontaining an elastomeric rubber portion surprisingly acts to improvethe handling properties and/or mechanical properties relative toconventional cements.

[0037] An inventive formulation is based on a polyacrylate, apolymerizable acrylate monomer and an elastomeric rubber toughener.While the polyacrylate and polymerizable acrylate monomer are admixedfrom a solid component pack and liquid component pack, respectively, itis appreciated that the elastomeric rubber toughener is provided ineither solid or liquid pack depending on such properties as liquid phasesolubility, molecular weight, and reactivity toward said polymerizableacrylate monomer.

[0038] As used herein, the term “polyacrylate” is defined to include allpolymers and copolymers of acrylic acid and acrylic acid esters that aresuitable for bone cements that include an acrylate monomer listedhereinbelow. Preferably, the ester is derived from an aliphatic C₁-C₆alcohol. More preferably, the ester is the methyl ester.

[0039] A polymerizable acrylate monomer as used herein is defined toinclude a methacrylate or acrylate monomer having at least oneunsaturated double bond. A polymerizable acrylate monomer according tothe present invention illustratively includes methyl methacrylate, ethylmethacrylate, isopropyl methacrylate, 2-hydroxyethyl methacrylate,n-butyl methacrylate, isobutyl methacrylate, 3-hydroxypropylmethacrylate, tetrahydrofurfuryl methacrylate, glycidyl methacrylate,2-methoxyethyl methacrylate, 2-ethylhexyl methacrylate, benzylmethacrylate, 2,2-bis(methacryloxyphenyl)propane,2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy)phenyl]propane,2,2-bis(4-methacryloxypolyethoxyl-phenyl)propane, ethylene glycoldimethacrylate, diethylene glycol dimethacrylate, triethylene glycoldimethacrylate, butylene glycol dimethacrylate, neopentyl glycoldimethacrylate, 1,3-butanediol dimethacrylate, 1,4-butanedioldimethacrylate, 1,6-hexanediol dimethacrylate, trimethylolpropanetrimethacrylate, trimethylolethane trimethacrylate, pentaerythritoltrimethacrylate, trimethylolmethane trimethacrylate and pentaerythtitoltetramethacrylate, and methacrylates and acrylates having urethane bondstherein. Specific urethane including acrylates includedi-2methacryloxyethyl-2,2,4-trimethylhexamethylene dicarbomate and itsacrylate. It is appreciated that phenyl ring containing acrylates arealso operative herein.

[0040] An elastomeric rubber toughener according to the presentinvention illustratively includes polyethylene, polypropylene,polybutene, polypentene, ethylene-propylene copolymers, isoprene-butenecopolymers, ethylene-butene copolymers, polybutadiene, polyisoprene,hydrogenated polybutadiene, hydrogenated polyisoprene,ethylene-propylene-diene copolymers, ethylene-butene-diene copolymers,butyl rubber, polystyrene, styrene-butadiene copolymers,styrene-hydrogenated butadiene copolymers, and ligand forms thereof at20° C.

[0041] A polymer bead core according to the present invention is definedto include a polymer or copolymer mass having a linear domain dimensionof from 0.1 microns to 500 microns and forming a stable interface with apolyacrylate overcoat. A polymer bead core illustratively includesacrylics, acrylates, styrenes, butadienes, alkylenes, carbonates, adipicacids, nylons, vinyl chlorides, urethanes, and isocyanates, andcopolymers thereof, especially with acrylates. More preferably, theacrylate copolymers are methyl methacrylate copolymers.

[0042] A solid component pack of an inventive bone cement formulationcontains from 3 to 25 solid component pack weight percent of apolyacrylate. Preferably, the polyacrylate is polymethyl methacrylate.The polyacrylate is preferably present from 3 to 20 solid component packweight percent. More preferably, the polyacrylate is present from 5 to15 solid component pack weight percent. The solid component pack alsocontains from 60 to 97 solid weight pack weight percent of F154 highimpact POLYMER CLEAR (Esschem, Inc.) where POLYMER CLEAR contains 0.38weight percent benzoyl peroxide, 9.9 weight percent barium sulfate and89.02 percent rubber toughened polymethyl methacrylate. An alternativeinventive solid component pack for an inventive cement formulationcontains 0.3 to 20 solid component pack weight percent of an elastomericrubber toughener and a polymer bead having a polyacrylate terminatedsurface.

[0043] A solid component pack according to the present invention alsooptionally contains a radiopaque agent in order to increase the x-raycontrast of the inventive bone cement formulations. Radiopaque agentsillustratively include calcium, strontium, barium, zirconium, and zincsulfates, oxides and mixtures thereof A radiopaque agent, if used, ispresent preferably from 5 to 15 solid component pack weight percent, andmore preferably from 5 to 10 solid component pack weight percent.

[0044] The solid component pack of an inventive bone cement formulationalso optionally includes a polymerization initiator. The initiator usedherein being selected from those known in the art and consistent withthe polymerizable acrylate monomer to be polymerized. Polymerizationinitiators operative herein illustratively include benzoyl peroxide,lauryl peroxide, methyl ethyl peroxide, diisopropyl peroxy carbonate,organometallic compounds, sulfinic acid derivatives, and tertiaryamines. The tertiary amines illustratively including dimethyl aminoethyl methacrylate, triethanol amine, 4-dimethyl amino benzoic acidmethyl, 4-dimethyl amino benzoic acid ethyl, and 4-dimethyl aminobenzoic acid isoamyl. An initiator, if used in the solid component pack,is present from 0.3 to 3.0 solid component pack weight percent.

[0045] The solid component pack of an inventive bone cement formulationalso optionally contains a biocompatibility additive. A biocompatibilityadditive includes antibiotics, bone morphogenetic protein,chemotherapeutic substances, hormones and mixtures thereof Theseadditives are selected from any of those known to the art andillustratively include gentamicin, cytostatic agents, calcitonin,aminoglycosides, cephalosporins, macrolides, and mixtures thereof.Specific antibiotics operative herein illustratively includeerythromycin, lyncomycin, clyndamycin, novobiocin, vancomycin, fusidinacid, rifampicin, polymycine, neomycin, kanamycin and tobramycin. Abioactive additive, if used, is present from 0.05 to 3 solid componentweight pack percent. It is appreciated that additional fillers,pigments, thixotropic agents and the like optionally are added to asolid component pack of an inventive cement formulation.

[0046] In a preferred embodiment, the solid component pack contains 93to 98 percent of polymer bead core having polymethylmethacrylateterminated surface, 1 to 3 percent polyalkylene copolymer elastomericrubber toughener, and 0 to 2.5 percent initiator, where percentages areweight percentages based upon solid component pack total weight percent.

[0047] An alternative preferred dry component pack of an inventivecement formulation contains 5 to 15 percent of polymethyl methacrylateadmixed with Esschem F154 high impact POLYMER CLEAR.

[0048] The liquid component pack of an inventive bone cement formulationcontains a polymerizable acrylate monomer. Preferably, the acrylatemonomer includes at least as a portion thereof methylmethacrylate.

[0049] The liquid component pack of an inventive bone cement formulationalso optionally contains an accelerator. The accelerator being chosenfrom those known to the art and illustratively includingN,Ndimethyl-p-toluidine; N,N-hydroxypropyl-p-toluidine; and mixturesthereof An accelerator, if used, is present from 0.2 to 3.0 liquidcomponent pack weight percent. More preferably, accelerator if used ispresent from 0.4 to 1.0 liquid component pack weight percent.

[0050] The liquid component pack of an inventive bone cement formulationoptionally also contains a polymerization inhibitor conventional to theart. A polymerization inhibitor operative herein illustratively includeshydroquinone, ascorbic acid, hydroquinone methyl ether and mixturesthereof. Hydroquinone is used in most commonly art and preferably usedherein. A polymerization inhibitor, when used, is present from 5 to 1000parts per million of the liquid component pack and more preferably from20 to 100 parts per million thereof.

[0051] Preferably, an inventive liquid component pack contains 97.4 to99.3 percent polymerizable methyl methacrylate, 0.5 to 3 weight percentN,N-dimethyl-p-toluidine, and 75 to 150 parts per million hydroquinone.

[0052] The rapid mixing and delivery of a bone cement prior to gellingand substantially free of air entrainment is critical to obtainingoptimal mechanical properties from a given bone cement. An inventivebone cement mixing and delivery system is illustrated in FIGS. 2-8. Acylinder tube 20 has three, tracks shown collectively at 22 within theinner wall 24 of the cylinder tube. The tracks 22 are spaced at 1200intervals. Cylinder tube 20 is constructed of materials illustrativelyincluding plastic, metal and glass and serves as a container for a bonecement liquid component pack and a bone cement solid component pack. Thecylinder tube 20 stores a liquid component pack in portion 20 a and asolid component pack in portion 20 b. It is appreciated that twoportions 20 a and 20 b can be stored separately yet combined to producea leakage-free seal. While it is appreciated that there are numerousmethods known to the art of fluid communication for selectively sealinglike inner diameter tubes, a preferred design in shown in FIG. 3. Tubeportion 20 a terminates in a flange 26. Tube portion 20 b terminates ina face adapted to secure against flange 26 directly or with a platetherebetween. A threaded collar 28 slides over the exterior 30 of tubeportion 20 b and engages the terminal face 27 of tube portion 20 b. Athreaded fitting 32 surrounds the exterior 31 of tube portion 20 a andengage the flange portion 26. The fitting 32 has threads complementaryto those of fitting 28 such that upon engagement of the fitting pair 28and 32, the flange 26 and the terminal face 27 are urged together toform a seal. The relative axial rotation between tube portions 20 a and20 b upon forming a seal therebetween is appreciated to be controlledthrough the use of an alignment pin, lock-key or other rotationalsymmetry disrupting mechanical feature. Three plates mount within thetube 20. Plate 1 has four needles 32 and three notches 34 therein. Plate1 has notches 34 spaced to engage the tracks 22 of tube portion 20 a. Asplate 1 moves along the length of tube portion 20 a, there is norotation of plate 1 unless tube portion 20 a itself rotates. Plate 1functions to seal a liquid component pack within tube portion 20 a.Plates 2 and 3 have highly polished surfaces such that a vacuum can bemaintained therebetween. Plate 2 has a series of holes 36 thereinwhereas plate 3 has a series of holes 38 uncoordinated from those ofplate 2. Plate 2 has notches 40 fitted to the tracks 22 of tube portion20 a. Plate 3 also has a series of symmetrically spaced notches 42 andthe notches of plate 3 engage a set of tracks 44 that are discontinuouswith the tracks 22 of tube portion 20 a, as shown in FIG. 4. Thus, whenone desires to mix the liquid contents of tube portion 20 a with thesolid component pack of tube portion 20 b, one rotates tube portion 20 arelative to tube portion 20 b thereby causing plate 2 to rotate relativeto plate 3 thereby bringing the holes 36 of plate 2 into alignment withthe holes 38 of plate 3. With hole alignment between plates 2 and 3, theliquid component pack stored in tube portion 20 a can pass through theholes 36 and 38. Preferably, tube portion 20 b has been previouslyevacuated and has a void volume equal to or greater than the volume ofthe liquid component pack in tube portion 20 a so as to spontaneouslydraw all the liquid stored in tube portion 20 a into tube portion 20 b.Thus, the liquid component pack and the solid component pack are mixedwithin tube portion 20 b. As the liquid component pack in tube 20 a isdrawn into tube portion 20 b, plate 1 is pulled into contact with plate2. The needles 32 of plate 1 penetrate the aligned holes 36 and 38, asshown in FIG. 6. The needles 32 on plate 1 serve as a stopper to preventbackward leakage of cement to tube portion 20 a and also allows threeplates to be rotated through an angle necessary for the notches 34, 36and 38 along track 44 with a pressure exerted by a conventionalinjection gun. Preferably, the track 44 is helical along the interior 30of tube portion 20 b to facilitate mixing and uniformity. Upon removinga seal from the applicator tip portion 50 of tube portion 20 b andexerting pressure on the rear face of plate 1 with an injector gun, auniformly mixed bone cement free of entrained air bubbles is deliveredthrough 50.

[0053] A bone cement formulation according to the present invention isdetailed in the following examples. These examples are intended to onlybe illustrative and nonlimiting as to the scope of the invention definedby the appended claims.

EXAMPLES Materials and Methods Example 1 Bone Cements

[0054] Simplex P bone cement was purchased from Howmedica InternationalInc. LUCITONE 199 was purchased from Caulk Dentistry (Milford, Del.).This particular impact modified acrylic powder is a copolymer of methylmethacrylate with butadiene and styrene, which is then coated with PMMA.F154 High Impact Polymer Clear (Esschem) was obtained from Esschem Inc.(Linwood, Pa.). This particular polymer is a rubber modified PMMA thatis used as a denture base in the dental field. It contains 0.38% benzoylperoxide (BPO). The particle size is 1% on 80 mesh, 1.5% on 100 mesh,8.6 on 150 mesh, 36.4% on 250 mesh, and 52.4% on pan. Coe-Tray PMMA(assigned as PMMA) was purchased from GC America Inc. (Chicago, Ill.).In addition, Polybutene (PB) (Mw=9,000 g/mol from GPC measurements,Macomer, Revertex Ltd. Harlow UK), a copolymer of isobutylene-butene,which consists predominately of high molecular weight polyolefins withminor isoparaffin content, was also used in formulation. Barium sulfate(BaSO₄), a radiopaque agent, was purchased from Acros Chemical Company.Benzoyl peroxide (BPO), hydroquinone (HQ) and methyl methacrylate (MMA,inhibited with 25 ppm±5 ppm HQ) were purchased from Fisher Scientific.N, N-Dimethyl-p-toluidine (N,N-DMPT) was purchased from Aldrich ChemicalCompany with a purity of 99%. All the chemicals were used as receivedand without further purification.

Example 2 Residual Monomer

[0055] A Perkin Elmer Sigma 3B GC with a Supelco 10% SP-2100 80/100 meshcolumn was employed to measure the residual monomer. A flame ionizationdetector was used to quantify the residual monomer amount. The injector,column and detector ports were set at 200, 185 and 190° C.,respectively. The flow rates of helium, hydrogen and air were adjustedso both MMA and EMA gave narrowest peak widths and noticeably differentelution times. The method employed a pentane or methylene chlorideextraction of ground cement powder, since the residual monomer issoluble in pentane but PMMA is not soluble. Methylmethacrylate (MMA) andethylmethacrylate (EMA) in pentane solutions were used to calibrate theinstrument and EMA was used as an internal standard. A 1 μl sample wasinjected into the gas chromatograph. The ratio of the MMA to the EMA wasdetermined by the height of the corresponding peaks from each of thechromatogram. The monomer content in the bone cement specimen wasdetermined from the calibration curve constructed from detector responsefactors obtained from a series of standard solution containing variousamount of MMA and fix amount of EMA. Each specimen was collected asthree samples from different areas of the specimens and each sample wasmeasured in triplicate.

Example 3 Size Exclusion Chromatography (SEC)

[0056] The molecular weight and molecular weight distributions weredetermined in both the powder and the formulated cements using acustomer made Waters size exclusion chromatography. A Waters HPLC pump(Waters, Model 590) was used for eluent delivery at 1.0 mL/min. A Waters410 differential refractometer was used as a concentration detector. Theinstrument was running at 25° C. and equipped with three WatersUltrastyragel HR3, HR4, and HR5 columns (Waters Corp. Milford, Mass.),measuring 30 cm in length and packed with 5 μm diameter PS Gel. The THFsolvent was filtered and degassed before use. Samples were dissolved inTHF at a concentration of 0.2˜0.4 mg/mL and preferably centrifugedbefore filtered with 0.2 μm pore size poly(tetrafluoroethylene) membranefilters (some rubber and radiopaque components could not be dissolved inTHF). Injection volumes of 100 μL were used. TriSEC software (ViscotekCo.) was used for data treatment. A series of eleven PMMA standards(Pressure Chemical Pittsburgh, Pa.) with their molecular weights rangingfrom 6000 to 1,600,000 were used to generate the calibration curve.

Example 4 Thermal Analysis

[0057] Differential scanning calorimetric analysis (DSC) was performedon a Mettler thermal analysis system with TC15 controller (MettlerToledo, Columbus, Ohio). Nitrogen atmosphere was applied.

Example 5 Hand Mixing

[0058] A series of formulations were prepared and compared with thecommercial bone cement formation Simplex P. The redox initiator wasblended with powder component and the redox accelerator was added to MMAmonomer. The room temperature powder and liquid components were added toa Stryker high vacuum cement injection system and mixed for 2 minutesfollowed by the transferring the dough under partial vacuum to acartridge and then injected into stainless steel molds for specimenformation.

Example 6 Tensile Testing

[0059] Specimens were prepared using the Stryker Advanced Cement MixingSystem. A double batch of cement was mixed and injected into the tensilemold. After the cement cured, “dog-bone” specimens (central reducedsection) were removed from the mold and placed in deionized water at 37°C. for 24 hours or 7 days.

[0060] Using a Sintech 2/G Screw Machine for testing, specimens wereplaced in the grips taking care to align the long axis of the specimenand grips in the same vertical plane. A 1.3 kN range load cell was usedto measure the applied load, global displacement was measured using themachine actuator displacement, and gage length displacement was measuredusing an externally applied extensometer. Specimens were loaded tofailure in uniaxial tension at a rate of 5 mm/min. The specimens weretested in air at room temperature immediately after removing them fromthe deionized water bath.

[0061] The tensile strength of the specimens was calculated by dividingthe maximum applied load by the original minimum cross-sectional area ofthe reduced section of the specimen. The tensile modulus was calculatedas the slope of the linear portion of the tensile stress-strain curve.The % elongation was calculated as the change in gage length divided bythe original gage length. Finally, the toughness was calculated as thearea under the stress-strain curve.

[0062] After testing, the fracture surface of the specimens was examinedfor any voids. Only specimens with voids less than 1 mm in diameter wereincluded since the interest was in the material properties of the bonecement. Since the strength of the bone cement is highly dependent on thesize of the defects at the fracture surface, specimens with large voidswould have a much lower tensile strength, tensile modulus, % elongation,and toughness, therefore, not a true representation of the materialproperties.

Example 7 Compressive Strength

[0063] Using the Stryker Advanced Cement Mixing System, a single unit ofcement was mixed and injected into the compression mold. After thecement had cured for 1 hour, cylindrical specimens (6 mm in diameter and12 mm in height) were removed from the mold and placed in deionizedwater at 37° C. for 24 hours or 7 days.

[0064] Mechanical testing was performed using a Sintech 2/G ScrewMachine with computer data acquisition and analysis. Specimens wereplaced in the fixture and tested to failure at a rate of 25.4 mm/min.They were tested immediately after removing them from the deionizedwater bath. Global displacement was measured using the machine actuatordisplacement.

[0065] The compressive strength of the specimens was calculated bydividing the load at failure by the original cross-sectional area of thecylinder. The load at failure was the 2% offset load. The compressivemodulus was calculated as the slope of the linear portion of thecompressive stress-strain curve.

Example 8 Fracture Toughness

[0066] A double batch of cement was mixed in a Stryker Advanced CementMixing System. The cement was injected into a stainless steelrectangular mold with a center notch and allowed to cure under pressure.Then the block was machined to produce single edge-notched specimenswith final dimensions of 6 mm W×12.5 mm T×63 mm L. All specimens wereaged in deionized water at 37° C. for 24 hours or 7 days before testing.

[0067] Testing was performed using a Sintech 2/G Screw Machine. A sharpcrack was introduced in the single edge-notched specimen immediatelybefore testing. The samples were tested at a crosshead speed of 0.5mm/min. Load versus displacement graphs were recorded, and the maximumload at fracture was measured for each specimen and used to calculatethe fracture toughness.

Example 9 Formulations

[0068] Various formulations based on LUCITONE are shown in Table 1.TABLE 1 Various Lucitone Formulations Formulation 1 Formulation 2Formulation 3 Plain Lucitone PB Modified Lucitone γ-Irradiated Lucitoneg g g Lucitone 199 65.8 Lucitone 199 65.1 Lucitone 199 36.0 (or PMMA)Polybutene 1.0 BaSO₄ 4.0 Benzoyl peroxide 0.65 Benzoyl peroxide 0.65Benzoyl peroxide 0.405 Methyl methacrylate 32.9 Methyl methacrylate 32.6Methyl methacrylate 18.0 N, N-DMPT 0.65 N, N-DMPT 0.65 N, N-DMPT 0.45

[0069] The handling properties of γ irradiated LUCITONE based cementformulation was further improved. In addition, the dispersion ability ofthe radiopaque agent BaSO₄ was improved. In some preliminaryformulations incorporating BaSO₄ and non-irradiated LUCITONE, thedispersion of BaSO₄ was very difficult, showing agglomeration and lackof wetting. The difficulty was overcome by blending the solid componentsin a Waring blender, followed by removal of clumps with a 350 μm sieve.The irradiated LUCITONE, with its low molecular weight, exhibits betterhandling characteristics including easier dispersion of BaSO₄.

Example 10 Molecular Weights

[0070] Molecular weight and molecular weight distribution of the bonecement before and after cured are listed in Table 2. TABLE 2 MolecularWeight and Residual Monomer Contents of Lucitone-Based Cements SampleCode M_(w) × 10⁻³ M_(n) × 10⁻³ M_(w)/M_(n) Residue (%) Simplex P 215 892.42 7.86 LCT 379 150 2.54 2.49 LCT rad 173 78 2.22 Simplex P 234 (4.3)90.5 (9.3) 2.59 3.88 (0.93) formulation LCT formulation 440 (33.5) 140(12.1) 3.14 3.29 (0.256) LCT/PB formulation 352 (8.54) 142 (2.42) 2.481.81 (0.47) LCT/rad 182 (1.84) 89 (1.41) 2.04 formulation

[0071] Different formulations resulted in tremendous molecular weightvariation based on SEC chromatograms. Pure LUCITONE formulation had thehighest molecular weight (about 224,000), much greater than that of theSimplex P control (about 160,000). The molecular weight of the PBmodified LUCITONE formulation is very close to the molecular weight ofthe pure LUCITONE formulation. The γ irradiated LUCITONE exhibitsmolecular weights very close to that of the Simplex P formulation.

[0072] More apparent difference is observed when the molecular weightdistributions are compared. A γ irradiated LUCITONE formulation showsvery uniform molecular weight distribution. Molecular weightdistribution of pure LUCITONE, on the other hand, shows a bimodalbehavior, which is more uniform than prior art DRG cements.⁹

[0073] The bimodal behavior of molecular weight distribution of thecements is caused by different molecular weights of PMMA powder andnewly polymerized matrix. There is an apparent change in the averagemolecular weight during curing. The inter-bead matrix has a differentaverage molecular weight than the pre-polymerized beads.

[0074] The molecular weight distributions of the inventive cementsbecame more uniform when 1% of polybutene is added. Comparing themolecular weights and molecular weight distribution of PB modifiedLUCITONE and pure LUCITONE cement, the gel effect for PB modifiedLUCITONE is not as pronounced as that in the pure LUCITONE formulation.Furthermore, the molecular weight of newly formed irradiated LUCITONEwas the smallest of the discussed formulations.

Example 11 Reactivity of Elastomeric Rubber Toughener TowardsPolyacrylate Addition

[0075] To examine whether or not polybutene, which has “reactive”unsaturated end groups, was covalently bonded into the cement,extractions were conducted using hexanes. A substantial amount ofpolybutene was isolated of Table 1, Formulation 2 from the cement (SECanalysis). This result shows that substantial amounts of polybutene arenot covalently bound into the acrylic cement but instead are physicallydispersed therein.

Example 12 Residual Monomer

[0076] A gas chromatography method was employed to determine theresidual monomer content. During the measurements, the gas pressure andthe temperature of the different compartments were optimized to obtainthe best peak resolution and signal/noise ratio. A typical chromatogramshows three peaks. Shortly after the n-pentane peak is the peakrepresenting impurities in the solvent, followed by the peaks of MMA andEMA. The calibration curve shows a linear relation between the peakheight and MMA content. Usually, the method with 5 points of regressiongenerates a curve with regression coefficient greater than 0.998. Theresidual monomer of the bone cement was determined by measurement ofextracted solution of bone cement. The residual monomer of theexperimental bone cement and the Simplex control are shown in Table 1.From Table 1, indicating that the residual monomer contents ofexperimental bone cements are systematically lower than that of SimplexP control.

[0077] In the GC method, the residual monomer was measured andcalculated based on the total mass of the specimens. In a bone cementsystem, polymer powder was not completely dissolved in monomer to form ahomogeneous phase during the mixing. Any undissolved PMMA powder wouldbe part of the total mass but not part of the reaction mass. For twobone cement formulations, even the residual monomer content of thereaction mass were the same, if the reaction mass ratio to the totalmass had been smaller, the total amount of residual MMA also would havebeen lower since the powder had a very low residual monomer content.Depending on the dissolution characteristics of the particular cement,undissolved powder could account for over half of the total mass of thematerial, based on Kusy's estimation¹³. Comparing the residual monomercontent of Simplex P, LUCITONE and PB modified LUCITONE, the higher therubber content in the cement formulation, the lower the residualmonomer. The presence of PB reduces the uptake of MMA into the powdermatrix.

[0078] In addition to the potential effects on mechanical properties,the presence of residual monomer has an adverse effect on the vicinalcell tissue around the bone cement.

Example 13 Mechanical Properties

[0079] Mechanical properties of inventive bone cements and the Controlare listed in Table 3. TABLE 3 Mechanical properties of the modifiedbone cements and Simplex P cement Notched Elastic Flexure FlexureFlexure Modulus Composition (MPw) Displacement (MPa) Compression (GPa)Simplex 66.60 (4.8)  7.87 (0.59) 39.1 (4.1)  85.7 (4.9) 1.93 (0.11)Lucitone 199 61.32 (4.5)  9.65 (1.2) 54.9 (8.99)  76.3 (4.9) 1.74 (0.10)PB modified 73.71 (2.64) 11.60 (0.7)  84.9 (2.6) 1.87 (0.11) Lucitone199 PB modified 57.44 (3.5)  5.5 (0.7)  84.9 (2.6) 1.98 (0.18) PMMALucitone  84.7 (6.58) 13.01 (8.8) 91.33 (1.93) 2.33 (0.21) Rad

[0080] Incorporating rubber toughened PMMA substantially increases thefracture toughness of bone cement. The plain LUCITONE group exhibitedimproved notched flexure strength and greater displacement over SimplexP control before fracture in the flexure test.

[0081] The most striking difference between the inventive formulationsand the conventional PMMA formulation is that many test bars fromLUCITONE based formation did not break when the flexure test wasperformed. The toughened material underwent complete yielding. Thisbehavior is strong evidence that toughened material exists in theformulation.

[0082] In the bone cement formulation, as discussed above, the powdercomponent was not totally dissolved in monomer before setting. There isa clear interface between the powder and the newly formed PMMA phase.¹⁹

[0083] Both mechanisms can be observed from the surface of the brokenspecimen of notched fracture testing either by microscopy or by using amagnifying glass. A Simplex P specimen showed flat propagation of thecrack with a smooth fracture surface morphology. Clearly, PMMA particlesexhibited brittle fracture and appeared to have been cleaved. For theLUCITONE formulation, the appearance of the fracture surface of theinventive cement was more irregular showing smooth and rough regions.The crack propagation path moved preferentially through the interbeadmatrix (newly formed PMMA) and fewer fractured beads are observed. Inthe smooth regions, the crack propagated directly through the beads andmatrix fracturing the particles. In the rough region the mechanismchanged to ductile tearing. The increase of plastic deformation of thecement matrix with rubber content could be detected macroscopicallybecause the plastically deformed zone ahead of the crack tip becamewhiter than the rest of the specimen.

[0084] AFM fractographs of conventional and rubber toughened bone cementare shown in FIGS. 7 through FIG. 10. Compared to conventional SEMfractographs, AFM fractographs reveal more details about the structureof the surface in 3-dimensional expression. FIG. 7 is the fracturesurface of the conventional bone cement. A relatively flat surface canbe observed, reflecting a brittle breakage mechanism. The surfacetexture was very much similar to that of flour dough that was pulledapart. A crazed structure can be seen in FIG. 8. The craze was parallelto the crack surface. The width of the fiber was about 5 μm. The fiberwas not perfect but contained holes, reflecting the three dimensionalstrength. When the bone cement was toughened by the addition of rubberymaterial, a brush-like structure can be observed (FIG. 9), which waspresumably caused by the ductile tearing of the matrix. The brush hairswere inevitably almost perpendicular to the crack surface. The mostapparent difference of the brush hairs as compared to the otherstructure was that the hairs were very much like carrots with smoothsurface and cylinder shape. The diameter of the cylinder was about 2 μm.Such structures were not observed for un-toughened material; however, itwas widely dispersed in the toughened materials. Elastic structure canbe observed from the toughened material as shown in FIG. 10.

[0085] Although the ductile material was increased in the formulation,the flexure and compressive strength of LUCITONE, however, were only 8%and 11% lower than that of Simplex P formulation, and the difference wasstatistically significant. This trend is consistent with the results ofVila et al. for ABS toughened bone cement.¹⁸ However, the reduction ofthe properties was not as significant as in Vila's formulation. Asexpected, the autopolymerized materials have significantly reducedvalues of flexure and compressive strength and elastic modulus ascompared to commercially extruded PMMA rod.¹⁹ LUCITONE based inventiveformulation powder beads are smaller and the interface is lessnoticeable. The adhesion force of smaller beads between the interfacesshould be greater than that of the large beads, as compared to prior artDRG formulations.

[0086] It was discovered that the mechanical properties of PB modifiedLUCITONE were further improved over that of plain LUCITONE formulations.Flexure strength, flexure displacement, compressive strength and elasticmodulus of inventive PB modified LUCITONE are greatly improved ascompared to pure LUCITONE formulations. Obviously, these effects cannotbe explained by the rubber toughened mechanism since the addition of PBwill make the material more ductile and lower tensile and comprisalstrength.

[0087] As a reference, PB modified PMMA (Coe-tray) formulations wereprepared. Many mechanical properties of PB modified PMMA were inferiorto those of the pure LUCITONE or Simplex P formulations. However,compressive strength and elastic modulus of PB modified PMMA areimpressively high. Both properties are important in bone cementformulation since the bone cements are required to withstandconsiderable compressive forces. The cement should be able to transmitthe imposed loads without failure during the lifetime inside the humanbody.

Example 14 Composition of SIMPLEX and Esschem Based Inventive BoneCement Formulations

[0088] In order to obtain novel bone cements, which have mechanical andchemical properties, superior to those of existing commercial PMMA-basedformulations but with good handling properties, new formulations basedon the rubber-toughened approach were designed but with differentstarting materials. Denture base resin Esschem was used in thisformulation to improve the overall properties of Simplex P bone cement.The description of the base prior art compositions is listed in Table 4.The inventive formulations based on the Esschem and Simplex P resins arelisted in Table 5. TABLE 4 Composition of Prior Art Base Esschem andSimplex P Bone Cement Formulations Composition wt. % Constituent SimplexP Esschem Powder BPO 1.19 1.09 BaSO₄ 10.00 9.90 PMMA 16.55 Rubbertoughened PMMA 89.02 P(MMA/ST) 72.26 Liquid S E N,N-DMPT 2.48 2.43Hydroquinone 75 ppm 125 or 75 ppm MMA 97.51 97.55

[0089] TABLE 5 Weight of the each component in inventive formulationsLiquid E Coe-Tray 75 ppm 125 ppm Sample Simplex P Esschem PMMA Liquid SHQ HQ Code Description (g) (g) (g) (g) (g) (g) S Simplex P 80 0 0 40 0 0S5E Simplex P 76 4 0 40 0 0 5% Esschem S10E Simplex 72 8 0 40 0 0 P 10%Esschem E46-0 Ess-46 0 80 0 0 0 46 E40-0 Ess-40 0 80 0 0 40 0 E46-5PEss-46 5% 0 76 4 0 0 46 PMMA E40-5P Ess-40 5% 0 76 4 0 40 0 PMMA E46-Ess-46 10% 0 72 8 0 0 46 10P PMMA E40- Ess-40 10% 0 72 8 0 40 0 10P PMMAE46- Ess-46 15% 0 68 12 0 0 46 15P PMMA E40- Ess-40 15% 0 68 12 0 40 015P PMMA

Example 15 Mixing Properties

[0090] A series of different compositions of Simplex P and Exxchemresins are formulated based on the ratios listed in Table 5. Theirmixing and handling properties are summarized in Table 6. The doughtimes, setting times and maximum temperatures are listed in Table 7.TABLE 6 Summary of Mixing and Handling Properties of Inventive BoneCement Formulations Time to Initial Initial Appearance Become ViscositySample Description Time Homogeneous Increase Transfer S Powdery clumps0-45 sec 45 sec  >1 min 3 S5E Powdery 0-40 sec 40 sec  >1 min 3 S10EPowdery, fluid 0-30 sec 30 sec  >1 min 3 E46-0 Center clumpy, fluid  0-1min  1 min  >1 min 2 E40-0 Very clumpy  0-2 min —   45 sec 4 E46-5PSmooth, fluid  0-1 min 10 sec  >1 min 1 E40-5P Center clumpy  0-2 min — >1 min 2 E46-10P Center clumpy  0-1 min  1 min — 1 E40-10P Slightlyclumpy  0-2 min —  >1 min 2 E46-15P Powdery clumps  0-1 min  1 min — 2E40-15P Center clumpy  0-1 min  1 min  >1 min 2

[0091] TABLE 7 Physical Properties of Experimental Bone CementFormulations Dough Time Temperature_(max) Setting Time Bone Cement (min)(° C.) (min.) S 4.50 (0.00) 77.80 (4.92) 10.98 (0.57) (prior art) S5E4.88 (0.53)  80.95 (12.23) 11.25 (3.22) S10E 4.25 67.20 11.20 E46-012.31 (2.38)  64.27 (5.25) 16.71 (3.25) (prior art) E40-0 8.56 (0.63)62.37 (1.64) 14.57 (1.38) (prior art) E46-5P 12.25 (1.77)  67.2  17.08E40-5P 9.88 (0.18) 60.55 (2.05) 15.73 (1.14) E46-15P 10.75 (1.09)  69.75(2.33) 16.43 (0.86) E40-15P 9.13 (0.88) 67.40 (9.90) 13.31 (0.34)

[0092] The experimental cement formulations mixed in a similar manner toSimplex P using the Stryker mixing apparatus. The mixing propertiesshowed notable differences. The 2:1 powder to liquid (P/L) ratio pureEsschem cement (E40-0) resulted in a higher viscosity mix that did notpossess a smooth consistency. In addition, it did not readily transferto the injection cartridge, leaving material on the stirring blade andwalls of the mixer. As reported in Table 7, the setting time and maximumtemperature met ISO or ASTM specifications.

[0093] To improve the mixing, a lower P/L ratio was investigated. Aratio of 1.74/1 powder/liquid formulation was used E46-0). By decreasingthe P/L ratio the viscosity of the mix decreased and the consistencybecame very smooth after 1 minute of mixing. Likewise, the transfer tothe injection cartridge was much easier, only requiring stirring totransfer the cement. With the increase in monomer content the cementstayed fluid too long.

[0094] Next, three different weight percents of PMMA were added toEsschem, 5, 10 and 15% (140-5P, E46-5P, E40-10P, E46-10P, E40-15P, andE46-15P). As the percentage of PMMA increased the time required for thematerial to become homogeneous decreased, the dough time decreased, andthe setting time decreased.

[0095] By modifying standard commercial orthopedic bone cement with 5 or10 weight percent rubber toughened polymer, mixing and handlingproperties remain basically unchanged. There was no significantdifference in physical properties such as dough time, maximumtemperature, or setting time when compared to Simplex P. Actually, thetime it took the cement to become homogeneous was decreased with theaddition of 5 or 10% Esschem. Dough time of the experimentalformulations occurred between 8 and 12 minutes as compared to 4.5minutes for Simplex P. Setting time also increased from 11 minutes forSimplex P to 13-18 minutes for the experimental formulations. Theinventive material appeared to be more temperature sensitive at elevatedtemperatures causing a significant reduction in setting time, usuallyless than 8 minutes. However, the maximum temperatures of theexperimental formulations were consistently less than Simplex P.

[0096] The temperature evolution during polymerization depends on therate of heat production and the rate of heat transference to thesurroundings through the conduction, radiation and convection. Shown inTable 8, an increasing L/P ratio increased the inhibitor/initiatorratio, which delays the beginning of the polymerization process. Themaximum temperature attained also increased with the L/P ratio. Therealso is a correlation between the maximum temperature and the dough timeand setting time, in that the higher the maximum temperature, theshorter the dough time and setting time.

Example 16 Molecular Weights and Residual Monomer

[0097] Clinically, all bone cements must be sterilized before use.Usually, a 2.5 Mrad γ irradiation or ethylene oxide is applied tosterilize the liquid and powder component¹⁶ after exposure to γradiation; many properties of bone cement may decrease.¹⁷ Among theseproperties, the weight average molecular weight (Mw), number averagemolecular weight (Mn), and molecular weight distribution (MWD) arereduced significantly after γ irradiation, as shown in Table 8. However,if polymer originated from the same batch of raw powder, the molecularweight differences for different batches of γ irradiated are notsignificant as shown in Table 9. This means that if the sterilizationprocedure is properly applied, consistent properties of powder can beobtained from different batches. In order to be in consistent inclinical practice, powder components used in the inventive formulationswere sterilized by γ irradiated before use. TABLE 8 Molecular weights,molecular weight distribution and residual monomer content of bonecements and their raw materials. Residual Materials Mn Mw Mw/Mn MonomerPlexiglass DRG 51.2 119 2.32 0.445 (Prior Art) Simplex P Powder 88.8 2152.42 8.43  (Prior Art) Esschem Powder 213 636 2.98 / (Prior Art) EsschemPowder 93.0 179 1.92 / Irradiated (2.9) (0.9) (Prior Art) Coe-Tray PMMA172 322 2.22 (Prior Art) S 68.1 169 2.48 3.832 (Prior Art) S5E 88.0 2072.35 3.723 (Prior Art) S10E 98.4 263 2.68 3.348 (Prior Art) E40-0 84.7233 2.75 3.014 (Prior Art) E46-0 85.6 252 2.94 3.332 (Prior Art) E40-5P72.7 218 2.99 3.037 E46-5P 83.6 233 2.78 3.278 E40-10P 75.7 232 3.072.789 E46-10P 107 278 2.60 3.035 E40-15P 85.7 234 2.73 3.034 E46-15P88.5 248 2.80 3.234

[0098] TABLE 9 Molecular weight of Esschem powder after sterilizationBatch No. Mn (× 10³) Mw (× 10³) Mw/Mn 98080601 93.6 181 1.93 9809180289.7 179 2.00 98091803 93.4 179 1.91 98092101 98.6 179 1.81 9809250190.0 179 1.99 98092901 93.7 178 1.90 Average 93.2 179 1.92 StandardDeviation 3.23 0.98 0.069

[0099] Molecular weight and molecular weight distribution information ondifferent inventive bone cement formulations are listed in Table 8.

[0100] Theoretically, the higher the molecular weight, the higher theviscosity of the system, and therefore the mixing and handling should beworse. However, since the powder does not dissolve in monomercompletely, mixing and handling properties are also dependent on theparticle size of powder, wetting ability of powder in monomer and humanoperation, etc. In fact, the mixing and handling properties wereimproved when 5 or 10% of Esschem (S5E and S10#), which has highermolecular weight and contains a less compatible rubber, was added toSimplex P formulation.

[0101]FIG. 11 shows that for sample S5E the amount of residual monomerreaches to its stable level quickly and thus cell toxicity is expectedto be low. The residual monomer amount was slightly lower in 37° C.water than that in air and their difference remained constant over 5 to20 hours of storage time. These results demonstrate that hardened bonecement contains unreacted monomer that at its surface can be evaporatedor leached out. The diffusion rate of residual monomer from inside thespecimen to its surface is relatively slow. After monomer near thesurface is leached out completely, the rate of monomer release to thesurrounding environment slows down.

Example 17 Thermal Properties

[0102] Glass transition temperature (Tg) of Esschem after irradiationwas 106° C., which is the characteristic Tg of PMMA.²³ Tg of curedEsschem (E40-0) was 91° C. Upon heating the cement sample at 200° C. for30 minutes under nitrogen and running the DSC again, Tg returned to 105°C. The above observations suggest that the major component of Esschem isPMMA. Tg of cured specimens were lower than Tg of PMMA. However, it canbe brought back to its original temperature if the specimen was heatedfor a period of time. This suggests that the residual monomer in thecement serves as plasticizer to reduce the Tg of PMMA. After treatmentat 200° C. the cement contained undetectable residual monomer. Since theisothermal DSC thermogram shows exothermic behavior, the post-curingreaction dominated rather than the evaporation of monomer.

[0103] Rubber cannot be detected by DSC because of its low percentage.Since the Tg of the resin was not influenced by rubber, it is surmisedthat rubber is immiscible with PMMA. The rubber domains enable thecement to adsorb more energy without breaking than for pure PMMA alone.

[0104] TGA thermograms of EssChem show two steps of mass loss that canbe assigned to the mass loss of rubber and PMMA. The final weight didnot go to zero because the degradation temperature of BaSO₄ is beyondthe experimental temperatures employed.

Example 18 Tensile Testing

[0105] As shown in Table 10, there were no statistically significantdifferences in tensile strength, tensile modulus, % elongation, ortoughness between Simplex P, Simplex P with 5% Esschem (S5E), andSimplex P with 10% Esschem (S10E). However, tensile properties didappear to increase upon addition of Esschem to Simplex P. When comparingSimplex P with 5% Esschem to Simplex P, there was a 19% increase intensile strength an 8% increase in tensile modulus, a 43% increase in %elongation, and a 78% increase in toughness. Likewise comparing SimplexP with 10% Esschem to Simplex P there was a 25% increase in tensilestrength, an 11% increase in tensile modulus, a 70% increase in %elongation, and a 139% increase in toughness. The influence on themechanical behavior of adding rubber toughened PMMA can be clearlyobserved from tensile strength measurements. TABLE 10 Comparison ofResults from Tensile Testing Tensile Tensile Strength Modulus %Elongation Toughness Sample Mpa Gpa mm/mm Nmm S 44.12 (8.33) 2.70 (0.35)2.03 (0.64) 304.53 (172.82) (prior art) S5E 52.56 (2.49) 2.91 (0.11)2.90 (0.47) 541.97 (134.87) S10E 55.14 (1.76) 2.99 (0.01) 3.45 (0.62)726.50 (202.13)

Example 19 Compressive Strength Determination

[0106] Compressive properties are important to bone cements since bonecement serves as the intermediate to transfer load between bone andprosthesis. It must therefore withstand considerable compressive force.Results in Table 11 show that all rubber toughened experimentalformulations meet the compression standard for bone cement as specifiedin ISO Standard 5833 and ASTM Standard F 451. TABLE 11 Comparison ofResults from Compression Testing Number of Compressive ModulusCompressive Strength Bone Specimens (n) (GPa) (MPa) Cement 24 hours 7days 24 hours 7 days 24 hours 7 days S 26 24 2.55 (0.14) 2.55 (0.06)105.3 (9.15) 104.3 (8.44) (prior art) E46-0 23 25 2.13 (0.05) 2.23(0.04) 84.20 (2.82) 89.16 (4.30) (prior art) E40-0 28 29 2.15 (0.06)2.14 (0.08) 87.96 (2.43) 88.96 (4.48) (prior art) E46-5P 21 12 2.25(0.05) 2.27 (0.04) 88.39 (3.52) 91.85 (4.39) E40-5P 7 9 2.12 (0.03) 2.27(0.02) 89.31 (1.01) 95.63 (1.06) E46-10P 12 — 2.16 (0.06) — 84.20 (2.30)— E40-10P 12 13 2.22 (0.02) 2.29 (0.02) 92.75 (1.56) 93.91 (1.68)E46-15P 17 12 2.20 (0.07) 2.30 (0.03) 90.21 (2.49) 93.41 (2.25) E40-15P13 9 2.26 (0.05) 2.24 (0.03) 94.37 (2.89) 92.77 (2.30)

Example 20 Fracture Toughness

[0107] The results obtained for the fracture toughness of theexperimental formulations are shown in Table 12. The fracture toughnessincreased with increasing percentage of rubber-toughened polymer. Theserubber particles actually absorbed energy prior to fracture, and,therefore decreased the probability that the crack attained the criticallength for fracture. Rubber particles acted as a barrier to microcrackpropagation by deforming more than the PMMA matrix, consequentlyabsorbing more energy. The crack propagated mainly within the matrixsurrounding the rubber beads. This explained the increase in fracturetoughness for increased amounts of Esschem. TABLE 12 Comparison ofFracture Toughness Results Number of Specimens Fracture Toughness (n)(Mpam^(1/2)) Bone Cement 24 hours 7 days 24 hours 7 days S 14  4 1.94(0.10) 1.54 (0.29) (prior art) S5E 6 — 2.21 (0.30) — S10E 4 — 2.15(0.20) — E46-0 12  7 2.78 (0.45) 2.51 (0.21) (prior art) E40-0 13  72.48 (0.29) 2.34 (0.21) (prior art) E46-5P 7 — 2.51 (0.25) — E40-5P 5 —2.34 (0.15) — E46-15P 6 7 2.28 (0.29) 2.12 (0.09) E40-15P — 6 — 2.05(0.07)

[0108] Analysis of the fracture surfaces of conventional bone cement(Simplex P) versus the rubber modified cement (Esschem) revealed thatthe fracture mechanism changed as the Esschem content increased. SimplexP showed flat propagation of the crack with a smooth fracture surfacemorphology. PMMA particles exhibited brittle fracture and appeared to becleaved. The appearance of the fracture surface of the rubber-modifiedcement was more irregular, showing smooth and rough regions. In thesmooth regions the crack propagated directly through the beads andmatrix fracturing the particles. In the rough region the mechanismchanged to ductile tearing.

[0109] Patents and publications mentioned in the specification areindicative of the levels of those skilled in the art to which theinvention pertains. These patents and publications are incorporatedherein by reference to the same extent as if each individual patent orpublication was specifically and individually incorporated herein byreference.

[0110] The foregoing description is illustrative of particularembodiments of the invention, but is not meant to be a limitation uponthe practice thereof. The following claims, including all equivalentsthereof, are intended to define the scope of the invention.

1. A bone cement formulation comprising: a solid component packcomprising from 3 to 25 solid component pack weight percent of apolyacrylate and between 53.5 and 86.3 solid component pack weightpercent of rubber toughened polymethyl methacrylate having a rubbertoughener selected from the group consisting of: polyethylene,polypropylene, polybutene, polypentene, ethylene-propylene copolymers,isoprene-butene copolymers, ethylene-butene copolymers, polybutadiene,polyisoprene, hydrogenated polybutadiene, hydrogenated polyisoprene,ethylene-propylene-diene copolymers, ethylene-butene-diene copolymers,butyl rubber, polystyrene, styrene-butadiene copolymers,styrene-hydrogenated butadiene copolymers, and ligand forms thereof at20° C.; and a liquid component pack comprising an acrylate monomer. 2.The formulation of claim 1 wherein said polyacrylate is an acrylic acidester of an aliphatic C₁-C₂ alcohol.
 3. The formulation of claim 1wherein said acrylate monomer is selected from a group consisting of:methyl methacrylate, ethyl methacrylate, isopropylmethacrylate,2-hydroxyethyl methacrylate, n-butyl methacrylate, isobutylmethacrylate, 3-hydroxypropyl methacrylate, tetrahydrofurfurylmethacrylate, glycidyl methacrylate, 2-methoxyethyl methacrylate,2-ethylhexyl methacrylate, benzyl methacrylate,2,2-bis(methacyloxyphenyl)propane,2,2-bis[4-2-hydroxy-3-methacryloxypropoxy) phenyl]propane,2,2-bis(4-methacryloxypolyethoxylphenyl)propane, ethylene glycoldimethacrylate, diethylene glycol dimethacrylate, triethylene glycoldimethacrylate, butylene glycol dimethacrylate, neopentyl glycoldimethacrylate, 1,3-butanediol dimethacrylate, 1,4-butanedioldimethacrylate, 1,6-hexanediol dimethacrylate, trimethylolpropanetrimethacrylate, trimethylolethane trimethacrylate, pentaerythritoltrimethacrylate, trimethylolmethane trimethacrylate and pentaerythritoltetramethacrylate.
 4. The formulation of claim 1 wherein saidpolyacrylate is polymethyl methacrylate.
 5. The formulation of claim 1wherein said acrylate monomer is methyl methacrylate.
 6. The formulationof claim 1 wherein said solid component pack further comprises apolymerization initiator.
 7. The formulation of claim 1 wherein saidliquid component pack further comprises a polymerization accelerant. 8.The formulation of claim 1 or 6 wherein said solid component packfurther comprises a radiopaque agent.
 9. The formulation of claim 1 or 7wherein said liquid component pack further comprises a polymerizationinhibitor.
 10. A bone cement formulation comprising a solid componentpack comprising: 0.3 to 20 solid component pack weight percent of anelastomeric rubber toughener, and a polymer bead core component having apolyacrylate terminated surface; and a liquid component pack comprisingan acrylate monomer.
 11. The formulation of claim 10 wherein saidpolymer bead core is selected from a group consisting of acrylics,acrylates, styrenes, butadienes, alkylenes, carbonates, adipic acids,nylons, vinyl chlorides, urethanes, isocyanates and copolymers thereof.12. The formulation of claim 10 wherein said elastomeric rubbertoughener is selected from a group consisting of: polyethylene,polypropylene, polybutene, polypentene, ethylene-propylene copolymers,isoprene-butene copolymers, ethylene-butene copolymers, polybutadiene,polyisoprene, hydrogenated polybutadiene, hydrogenated polyisoprene,ethylene-propylene-diene copolymers, ethylene-butene-diene copolymers,butyl rubber, polystyrene, styrene-butadiene copolymers,styrene-hydrogenated butadiene copolymers, and ligand forms thereof at20° C.
 13. The formulation of claim 10 wherein said elastomeric rubbertoughener is present from 5-15 solid component pack weight percent. 14.The formulation of claim 10 wherein said polyacrylate terminated surfaceterminates in polymethyl methacrylate.
 15. The formulation of claim 10wherein said solid component pack further comprises a polymerizationinitiator.
 16. The formulation of claim 10 wherein said liquid componentpack further comprises a polymerization accelerant.
 17. The formulationof claim 10 or 16 wherein said solid component pack further comprises aradiopaque agent.
 18. The formulation of claim 10 or 17 wherein saidliquid component pack further comprises a polymerization inhibitor. 19.A method of fixing a prosthetic implant to a patient's bone whichcomprises applying a bone cement formulation as claimed in claim 1 to aprosthesis attachment site.
 20. A commercial package comprising a solidcomponent pack and a liquid component pack according to claim 1 togetherwith instructions for the use thereof as a bone cement.
 21. (Cancelled)22. A cement mixing and delivery system comprising: a tube having anexit nozzle and an aperture; a first end plate adapted to seal againstthe interior of the tube aperture, wherein the plate has a plurality ofneedles protruding therefrom into said tube; a rotatable and slidabledivider adapted to be received within said tube, said divider comprisingtwo plates, each of the two plates having a plurality of apertures suchthat upon alignment, the needles of said first plate upon being urgedthrough said tube engagee the apertures of the two divider plates. 23.The system of claim 22 wherein said tube has interior tracks adapted toengage the interior of said tube.
 24. The system of claim 22 whereinwherein a liquid component pack is stored on one side slidable dividerand a solid component pack is stored on the other side of said divider.25. The system of claim 24 wherein the solid component pack storedadjacent to the edit nozzle.
 26. The system of claim 25 wherein saidexit nozzle is sealed and said solid component pack is evacuated.
 27. Acement mixing and delivery system according to claim substantially asdescribed herein with reference to and/or as illustrated in theaccompanying drawings.
 28. A method of fixing a prosthetic implant to apatient's bone which comprises applying a bone cement formulation asclaimed in claim 10 to a prosthesis attachment site.
 29. A commercialpackage comprising a solid component pack and a liquid component packaccording to claim 10 together with instruction for the use thereof as abone cement.